Transporters for the monoamines dopamine, serotonin and norepinephrine are principal targets for the majority of antidepressant drugs such as fluoxetine/Prozac (serotonin transporter), methylphenidate/Ritalin (dopamine transporter), the most frequently prescribed drug for Attention Deficit Hyperactivity Disorder, and cocaine Without exception, the molecular structure of therapeutic and other drugs that modulate monoamine transporters contains an amine nitrogen We recently reported that the amine nitrogen can be exchanged for oxygen (aryloxatropanes, 8-oxa-bicyclo-3-aryl-[3 2 1 ]octanes) and retain potent inhibition of the dopamine, serotonin and/or norepinephrine transporters in monkey brain Oxygen-induced hydrogen bonding to substitute for amine-induced ionic bond formation was proposed as a mechanism to account for high affinity of this class of non-amines To investigate whether even hydrogen bonding is necessary, we replaced the oxygen with a carbon atom We now repo rt that several carbon-based compounds displayed high affinity binding for the dopamine transporter, including O-1231 (IC50 7 1 q 1 7nM), O-1414 (IC50 9 6 q 1 8 nM), O-1442 (IC50 14 3 q 1 1 nM) O-1231, which contains a flattened 2,3-unsaturated bond in the ring structure, was > 700-fold selective for the dopamine (DAT) over the serotonin (SERT) transporter O-1414, a saturated analog of O1231 in the 3- form ("chair") was only 3-fold selective for the DAT over the SERT whereas its 3-` analog ("boat") was > 10-fold Five conclusions can be drawn from these data Conformation of a molecule plays a significant role in conferring DAT or SERT affinity Orientation of the 3-aryl ring and the orientation of the 2-carbomethoxy ring relative to the aromatic ring is critical for alignment with the transporter Development of transporter-selective drug therapies for neuropsychiatric diseases can be guided by appropriate orientation of the 3-aryl group 8-Carbatropanes display high affinity for monoamine transporters, indicating that a functionality corresponding to an amine nitrogen is not necessary for anchoring the molecule to its target protein and blockade of monoamine transporters Within this series, transporter affinity appears to be largely sustained by the aromatic ring The DAT may have multiple binding sites for tropanes, while the SERT may be less flexible Ongoing research with mutant forms of the DAT will explore this premise This research has several implications First, it will clarify the feasibility of developing cocaine antagonists targeted to the dopamine transporter Second, it will help to clarify the molecular mechanisms by which drugs block monoamine transport Finally, these compounds have created a new generation of transporter drugs